RADIOLABELLED mGluR2 PET LIGANDS

Abstract

The present invention relates to novel, selective, radiolabelled mGluR2 ligands which are useful for imaging and quantifying the metabotropic glutamate receptor mGluR2 in tissues, using positron-emission tomography (PET). The invention is also directed to compositions comprising such compounds, to processes for preparing such compounds and compositions, to the use of such compounds and compositions for imaging a tissue, cells or a host, in vitro or in vivo and to precursors of said compounds.

1 . A compound according to Formula (I) 
       
         
           
           
               
               
           
         
         or a stereoisomeric form thereof, wherein 
         R 1  is selected from the group consisting of cyclopropylmethyl and C 1-3 alkyl substituted with one or more fluoro substituents; 
         R 2  is selected from chloro and trifluoromethyl; 
         R 3  is fluoro; 
         n is selected from 0, 1 and 2; 
         wherein at least one C is [ 11 C]; 
         or a salt or thereof. 
       
     
     
         2 . The compound according to  claim 1 , having the formula [ 11 C]-(I) 
       
         
           
           
               
               
           
         
         or a stereisomeric form thereof, wherein
 R 1  is selected from the group consisting of cyclopropylmethyl and C 1-3 alkyl substituted with one or more fluoro substituents; 
 R 2  is selected from chloro and trifluoromethyl; 
 R 3  is fluoro; 
 n is selected from 0, 1 and 2; 
 
         or a salt thereof. 
       
     
     
         3 . The compound according to  claim 1  wherein
 R 1  is selected from cyclopropylmethyl and 2,2,2-trifluoroethyl; and 
 R 2  is selected from chloro and trifluoromethyl. 
 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is cyclopropylmethyl and R 2  is chloro. 
     
     
         5 . The compound according to  claim 1 , wherein n is 0 or 2. 
     
     
         6 . The compound according to  claim 1 , selected from the group consisting of
 8-chloro-3-(cyclopropylmethyl)-7-[4-[5-fluoro-2-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-[2-fluoro-6-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-7-[4-[5-fluoro-2-[ 11 C]methoxyphenyl]-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-7-[4-[2-fluoro-6-[ 11 C]methoxyphenyl]-1-piperidinyl]-3-(2,2,2-trifluoroethyl)-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-[2,4-difluoro-6-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-(3,6-difluoro-2-[ 11 C]methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-[2,3-difluoro-6-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-[3-fluoro-2-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-[2-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-[3,4-difluoro-2-[ 11 C]methoxyphenyl]-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   3-(cyclopropylmethyl)-7-[4-[3-fluoro-2-[ 11 C]methoxyphenyl]-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine, and   3-(cyclopropylmethyl)-7-[4-[3,6-difluoro-2-[ 11 C]methoxyphenyl]-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine;   
       or a stereoisomeric form, or a salt or a solvate thereof. 
     
     
         7 . A sterile solution comprising a compound of Formula (I) as defined in  claim 1 . 
     
     
         8 . (canceled) 
     
     
         9 . A method of imaging a tissue, cells or a host, comprising contacting with or administering to a tissue, cells or a host, a compound of Formula (I) as defined in  claim 1 , and imaging the tissue, cells or host with a positron-emission tomography imaging system. 
     
     
         10 . A compound according to formula (V) 
       
         
           
           
               
               
           
         
         or a stereisomeric form thereof, wherein
 R 1  is selected from the group consisting of cyclopropylmethyl and C 1-3 alkyl substituted with one or more fluoro substituents; 
 R 2  is selected from chloro and trifluoromethyl; 
 R 3  is fluoro; 
 n is selected from 0, 1 and 2; 
 
         or a salt thereof; 
         with the proviso that 2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-4-fluoro-phenol is excluded. 
       
     
     
         11 . The compound according to  claim 10 , wherein n is 0 or 2. 
     
     
         12 . The compound according to  claim 10 , selected from the group consisting of
 2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-3-fluoro-phenol,   2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-3,6-difluoro-phenol,   2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-3,5-difluoro-phenol,   2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-3,4-difluoro-phenol, and   2-[1-[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-3,6-difluoro-phenol;   
       or a stereoisomeric form, or a salt thereof. 
     
     
         13 . A process for the preparation of a compound according to Formula [ 11 C]-(I), 
       
         
           
           
               
               
           
         
         or a stereisomeric form thereof, wherein 
         R1 is selected from the group consisting of cyclopropylmethyl and C1-3 alkyl substituted with one or more fluoro substituents; 
         R2 is selected from chloro and trifluoromethyl; 
         R3 is fluoro; 
         n is selected from 0, 1 and 2; 
         or a salt thereof.
 comprising the step of reacting a compound according to formula (V) 
 
       
       
         
           
           
               
               
           
         
       
       or a stereisomeric form thereof, wherein
 R1 is selected from the group consisting of cyclopropylmethyl and C1-3 alkyl substituted with one or more fluoro substituents; 
 R2 is selected from chloro and trifluoromethyl; 
 R3 is fluoro; 
 n is selected from 0, 1 and 2; 
 or a salt thereof; 
 with the proviso that 2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-4-fluoro-phenol is excluded. 
 with [ 11 C]CH 3 I or [ 11 C]CH 3 OTf in the presence of a base in an inert solvent to form [11C]-(I) 
 
       
         
           
           
               
               
           
         
       
     
     
         14 . A process for the preparation of a compound according to Formula (V), 
       
         
           
           
               
               
           
         
         or a stereisomeric form thereof, wherein 
         R1 is selected from the group consisting of cyclopropylmethyl and C1-3alkyl substituted with one or more fluoro substituents; 
         R2 is selected from chloro and trifluoromethyl; 
         R3 is fluoro; 
         n is selected from 0, 1 and 2; 
         or a salt thereof; 
         with the proviso that 2-[1-[8-chloro-3-(cyclopropylmethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]-4-piperidinyl]-4-fluoro-phenol is excluded.
 comprising 
 
         (a) the step of reacting a compound according to formula [ 12 C]-(I), with a Lewis acid selected from boron trichloride or boron tribromide in the presence of an inert solvent 
       
       
         
           
           
               
               
           
         
         or 
         (b) the step of reacting a compound according to formula (XX) with a compound of formula (IV), in the presence of a suitable base, in an inert solvent 
       
       
         
           
           
               
               
           
         
         wherein
 R 1  is selected from the group consisting of cyclopropylmethyl and C 1-3 alkyl substituted with one or more fluoro substituents; 
 
         R 2  is selected from chloro and trifluoromethyl; 
         R 3  is fluoro; and 
         n is selected from 0, 1 and 2. 
       
     
     
         15 . A compound selected from the group consisting of
 8-chloro-3-(cyclopropylmethyl)-7-[4-(2,4-difluoro-6-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-(3,6-difluoro-2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-(2,3-difluoro-6-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-(3-fluoro-2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-(2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   8-chloro-3-(cyclopropylmethyl)-7-[4-(3,4-difluoro-2-methoxyphenyl)-1-piperidinyl]-1,2,4-triazolo[4,3-a]pyridine,   3-(cyclopropylmethyl)-7-[4-(3-fluoro-2-methoxyphenyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine, and   3-(cyclopropylmethyl)-7-[4-(3,6-difluoro-2-methoxyphenyl)-1-piperidinyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine;   
       or a stereoisomeric form, or a salt thereof.